Synthetic mechanical hemostatic composition, method of making and use thereof

ABSTRACT

A biocompatible, polymeric composition is disclosed. The composition comprises a base polymer comprising (i) a prepolymer comprising para-dioxanone (PDO) and trimethylene carbonate (TMC); and (ii) an end-graft polymer chain comprising a polylactone. Also disclosed are a method for treating bleeding from bone or bony structures using the composition, a method for filling a void or correct a defect in a bone using the composition, and a method for producing the biocompatible, polymeric composition of the present application.

FIELD

The present application relates generally to a synthetic composition,and more specifically, to synthetic mechanical hemostatic compositionsthat are suitable for a variety of medical applications.

BACKGROUND

Surgical bone wax is a relatively safe and inert hemostatic agent thatis commonly used in a variety of surgical procedures to mechanicallyplug bleeding bony structures and elicit immediate hemostasis. Sincecommercial bone wax typically consists of beeswax, isopropyl palmitateand softening agents such as paraffin, the material is minimallyresorbable and remains in the body for the lifetime of the patientfollowing surgery.

The continued post-operative persistence of bone wax is the mostcritical issue regarding the potential for future complications. Therehave been case reports of bone wax-related complications that includethe development of post-thoractomy paraplegia and tumor. The persistentforeign bone wax may also result in immune responses to the bone wax.Furthermore, the residual bone wax can migrate out of the original siteof application following surgery. Migrated bone wax can exertcompressive forces on the spinal cord, leading to debilitatingparaplegia that requires a second operative procedure to remove thedisplaced bone wax. Accordingly, there exits a need for the developmenta bone wax that is biocompatible and has similar physical properties toconventional bone wax.

SUMMARY

One aspect of the present application relates to a biocompatible,polymeric composition. The biocompatible, polymeric compositioncomprises a base polymer comprising (i) a prepolymer or first polymericsegment comprising para-dioxanone (PDO) and trimethylene carbonate(TMC); and (ii) an end-graft polymer chain or second polymeric segmentcomprising a polylactone. In further embodiments, the end-graft polymerchain or second polymeric segment comprises semicrystalline polylactonechain segments. In yet other embodiments, the polymeric compositions aresterile, and optionally, do not contain beeswax or other animal or humanproducts (such as, for example, collagen).

Another aspect of the present application relates to a method fortreating bleeding from bone or bony structures. The method comprises thestep of administering to a site of bleeding from bone or bony structuresin a subject an effective amount of the biocompatible, polymericcomposition of the present application.

Another aspect of the present application relates to a method forfilling a void or correct a defect in a bone. The method comprisesadministering to a void or defect in a bone of a subject an effectiveamount of the biocompatible, polymeric composition of the presentapplication, such that the void is filled or the defect is corrected.

Another aspect of the present application relates to a method forproducing the biocompatible, polymeric composition of the presentapplication. The method comprises the steps of: forming a prepolymer byadmixing para-dioxanone and trimethylene carbonate and polymerizing withan initiator; and end-capping the prepolymer with a compositioncomprising a polylactone.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a composite showing streak test comparison of commercialETHICON® bone wax vs. (A) TPDX1 and (B) TPDX2.

DETAILED DESCRIPTION

The following detailed description is presented to enable any personskilled in the art to make and use the invention. For purposes ofexplanation, specific nomenclature is set forth to provide a thoroughunderstanding of the present invention. However, it will be apparent toone skilled in the art that these specific details are not required topractice the invention. Descriptions of specific applications areprovided only as representative examples. Various modifications to thepreferred embodiments will be readily apparent to one skilled in theart, and the general principles defined herein may be applied to otherembodiments and applications without departing from the scope of theinvention. In addition, the disclosures of all patents and patentapplications referenced herein are incorporated by reference in theirentirety.

In case of conflict, the present specification, including definitions,will control. Following long-standing patent law convention, the terms“a,” “an” and “the” mean “one or more” when used in this application,including in the claims.

One aspect of the present application relates to a syntheticbiocompatible composition that comprises a base polymer comprising aprepolymer and an end-graft polymer In some embodiments, the end-graftpolymer comprises a polylactone.

In some embodiments, the synthetic biocompatible composition furthercomprises a biocompatible plasticizer. In some embodiments, thesynthetic biocompatible composition further comprises one or moretherapeutic agents. In some embodiments, the synthetic biocompatiblecomposition is a mechanical hemostatic polymeric composition that isentirely synthetic and does not contain any animal products, such asbees wax. In other embodiments, the synthetic biocompatible compositionis sterile.

In certain embodiments, the synthetic biocompatible composition can beused as a substitute for traditional bone wax. The syntheticbiocompatible composition is biocompatible and preferably bioabsorbable.When used as a bone wax in a surgical procedure, it does not increasethe infection rate normally associated with the procedure, does notinterfere with bone healing and does not cause additional inflammationbeyond those normally associated with the procedure.

The Base Polymers

The base polymer is a biocompatible polymer comprising a prepolymer andend-grafted polymeric chain segments. The term “biocompatible” as usedherein is intended to describe materials that do not elicit asubstantial detrimental response in vivo. In some embodiments, thebiocompatible polymer is also a “bioabsorbable polymer.” The teen“bioabsorbable polymer” refers to a polymer that can be broken down byeither chemical or physical process in an in vivo setting, uponinteraction with the physiological environment at a treatment site, anderodes or dissolves within a period of time. The rate of degradation ismostly determined by the chemical structure of the polymer, as well asthe local environment. A bioabsorbable polymer serves a temporaryfunction in the body, such as plugging bleeding bony structures andeliciting immediate hemostasis, or delivering a drug, and is thendegraded or broken into components that are metabolizable or excretable.

Examples of bioabsorbable polymers include, but are not limited to,polyglycolic acid (PGA), polylactic acid (PLA), lactic acid-glycolicacid copolymer (PLGA), polyethylene terephthalate (PET),polyglycolide-lactide, polycaprolactone (PCL), lacticacid-ε-caprolactone copolymer (PLCL), polydioxanone (PDO),polytrimethylene carbonate (PTMC), polydioxanone, polyoxalate andcopolymers thereof.

Suitable bioabsorbable polyester copolymers include, but are not limitedto, lactide/glycolide copolymers, caprolactone/glycolide copolymers,lactide/trimethylene carbonate copolymers,lactide/glycolide/caprolactone terpolymers,lactide/glycolide/trimethylene carbonate terpolymers,lactide/caprolactone/trimethylene carbonate terpolymers,glycolide/caprolactone/trimethylene carbonate terpolymers, andlactide/glycolide/caprolactone/trimethylene carbonate terpolymers.

In other embodiments, the bioabsorbable polymer comprises polyaxial,segmented co-polymers with non-crystallizable, flexible components ofthe chain at the core and rigid, crystallizable segments at the chainterminals. The bioabsorbable polymers are produced by reacting amorphouspolymeric polyaxial initiators with cyclic monomers. The amorphouspolymeric polyaxial initiators have branches originating from apolyfunctional organic compound so as to extend along more than twocoordinates and to copolymerize with the cyclic monomers. In someembodiments, the bioabsorbable copolymer comprises at least 30%, 50%,65%, 75%, 90% or 95% by weight, of a crystallizable component which ismade primarily of glycolide-derived or L-lactide-derived sequences.

In some embodiments, the amorphous polymeric, polyaxial initiators aremade by reacting a cyclic monomer or a mixture of cyclic monomers suchas trimethylene carbonate (TMC), caprolactone, and 1,5-dioxapane-2-onein the presence of an organometallic catalyst with one or morepolyhydroxy, polyamino, or hydroxyamino compound having three or morereactive amines and/or hydroxyl groups. Typical examples of the lattercompounds are glycerol and ethane-trimethylol, propane-trimethylol,pentaerythritol, triethanolamine, and N-2-aminoethyl-1,3-propanediamine.

The flexible polyaxial prepolymer can be derived from para-dioxanone,1,5-dioxepan-2-one, or one of the following mixtures of polymers: (1)trimethylene carbonate and para-dioxanone with or without a small amountof glycolide; (2) trimethylene carbonate and a cyclic dimer ofpara-dioxanone with or without a small amount of glycolide; (3)caprolactone and para-dioxanone with or without a small amount ofglycolide; (4) trimethylene carbonate and caprolactone with or without asmall amount of D,L-lactide; (5) caprolactone and D,L-lactide (ormeso-lactide) with or without a small amount of glycolide; and (6)trimethylene carbonate and D,L-lactide (or meso-lactide) with or withouta small amount of glycolide. Further, the crystallizable segment can bederived from para-dioxanone. Alternate precursors of the crystallizablesegment can be a mixture of predominantly para-dioxanone with a minorcomponent of one or more of the following monomers: glycolide, L-lactide1,5-dioxepan-2-one, trimethylene carbonate, and caprolactone.

In other embodiments, the bioabsorbable polymer is an ABA-type triblockpolymer, where A is L-lactide/glycolide and B is PEG. In certainembodiments, the absorbable polymer fiber comprises a polyaxial,segmented biodegradable copolyester. In other embodiments, theabsorbable polymer comprises a L-lactide/caprolactone coploymer, aL-lactide/trimethylene carbonate coploymer, aglycolide/L-lactide/trimethylene carbonate copolymer coploymer, aL-lactide/caprolactone/trimethylene carbonate coploymer or combinationsthereof. In one embodiment, the absorbable polymer comprises ahomopolymer of polydioxanone. In another embodiment, the absorbablepolymer comprises a glycolide/L-lactide/trimethylene carbonatecopolymer. In another embodiment, the absorbable polymer comprises aPEG/glycolide/L-lactide copolymer.

In some other embodiments, the bioabsorbable polymer is a uniaxialpolymer. Examples of uniaxial polymers include, but are not limited to,a homopolymer of polydioxanone, poly glycolic acid, polyglycolide,polylactide (L-, D-, or meso-), trimethylene carbonate,polycaprolactone, and copolymers thereof.

In certain embodiments, the bioabsorbable polymer is a solid crystallinepolyaxial coploymer comprising a polyaxial prepolymer andsemicrystalline end graft, which is referred to herein after as TPDXpolymer. The term “semicrystalline” refers to a crystallinity of greaterthan 5 J/g as measured by differential scanning calorimetry (DSC). Insome embodiments, the term “semicrystalline” refers to a crystallinityof 20-70 J/g as measured by differential scanning calorimetry (DSC).

In some embodiments, the polyaxial prepolymer comprises polymerizedtrimethylene carbonate (TMC) and para-dioxanone (PDO) and is initiatedwith trimethylopropane; while the end graft comprises polymerizedL-lactide and para-dioxanone. The prepolymer constitutes approximately10-40%, preferably 15-35%, more preferably 20-30%, most preferably 25%by mole of the bioabsorbable polymer. The end-graft constitutesapproximately 60-90%, preferably 65-85%, more preferably 70-80%, mostpreferably 75% by mole of the bioabsorbable polymer. In one embodiment,the composition of the prepolymer is TMC/PDO (17.1/8.6% by mole), andthe end graft composition is L-lactide/PDO (5.9/68.3% by mole).

In other embodiments, the polyaxial prepolymer comprises polymerizedtrimethylene carbonate (TMC) and para-dioxanone (PDO) and is initiatedwith trimethyopropane; while the end graft comprises polymerizedglycolide and para-dioxanone. The prepolymer constitutes approximately10-40%, preferably 15-35%, more preferably 20-30%, most preferably25-26% by mole of the bioabsorbable polymer. The end-graft constitutesapproximately 60-90%, preferably 65-85%, more preferably 70-80%, mostpreferably 74-75% by mole of the bioabsorbable polymer. In oneembodiment, the composition of the prepolymer is TMC/PDO (16.7/8.3% bymole), and the end graft composition is glycolide/PDO (11.2/63.8% bymole). In another embodiment, the prepolymer constitutes approximately25% by mole of the bioabsorbable polymer, the end-graft constitutesapproximately 75% by mole of the bioabsorbable polymer, and thecomposition of the prepolymer is TMC/PDO (17.1/8.6% by mole), and theend graft composition is glycolide/PDO (4.5/69.8% by mole).

In other embodiments, the prepolymer consists of polymerized PDO,glycolide and trimethylene carbonate (TMC) and is initiated withtrimethylolpropane. The end graft consists of polymerized glycolide andpara-dioxanone. The prepolymer constitutes approximately 30-60%,preferably 35-55%, more preferably 40-50%, most preferably 45% by moleof the polymer, and the end-graft constitutes approximately 40-70%,preferably 45-65%, more preferably 50-60%, most preferably 55% by mole.In one embodiment, the composition of the prepolymer isglycolide/TMC/PDO (14.8/14.5/15.8% by mole), and the end graftcomposition is glycolide/PDO (8.2/46.8% by mole).

The amount of initiator (e.g., trimethylopropane) may vary in differentcrystalline polyaxial copolymer preparations. The larger is the amountof the initiator, the smaller is the molecular weight of the copolymer.In some embodiments, the prepolymer is prepared with amonomer-to-initiator mole ratio in the range of 30:1 to 100:1. In oneembodiment, the prepolymer is prepared with a monomer-to-initiator moleratio in the range of 35:1. In another embodiment, the prepolymer isprepared with a monomer-to-initiator mole ratio in the range of 100:1.

In other embodiments, the prepolymer consists of polymerized PDO andtrimethylene carbonate (TMC), and the end-graft polymer comprises apolylactone. In one embodiment, the end-graft polymer further comprisespara-dioxanone. In another embodiment, the polylactone comprises a polyL-lactide. In another embodiment, the polylactone comprises apoly-glycolide. In other embodiments, the polylactone is a polymer otherthan poly L-lactide or poly-glycolide. For example, in one embodiment,the polylactone comprises a copolymer of (1) para-dioxanone repeat unitsand (2) repeat units of at least one other cyclic monomer. In a relatedembodiment, the at least one other cyclic monomer is selected from thegroup consisting of L-lactide, D-lactide, D,L-lactide, glycolide,caprolactone and trimethylene carbonate.

In other embodiments, the TPDX polymer is a solid crystalline polyaxialcopolymer comprising a polyaxial prepolymer, semicrystalline end graftand a third outer segment comprising poly(trimethylene carbonate). Inone embodiment, such a bioabsorbable polymer is prepared by reacting (1)a purified polyaxial copolymer comprising a polyaxial prepolymer ofpara-dioxanone and trimethylene carbonate initiated withtrimethylolpropane, and semicrystalline end graft consists ofpolymerized glycolide and para-dioxanone with (2) trimethylenecarbonate. In some embodiments, the purified polyaxial copolymer isreacted with trimethylene carbonate at a weight ratio of 1:1 to 9:1. Inone embodiment, the purified polyaxial copolymer is reacted withtrimethylene carbonate at a weight ratio of 3:1.

In some embodiments, the absorbable polymer comprises two or moredifferent types of TPDX polymers. For instance, a highly crystallineTPDX may be blended with a less crystalline and semi-liquid TPDX toyield a compliant putty-like blend. In other embodiments, the absorbablepolymer comprises a TPDX polymer with other absorbable polyesters, suchas polyaxial poly(TMC) and/or low molecular weight poly(para-dioxanone).

In some embodiments, the number average molecular weight (Mn) of thebase polymer is in the range of 3000-10,000 dalton, preferably in therange of 4000-7000 dalton. In other embodiments, the weight averagemolecular weight (Mw) of the base polymer is in the range of 5000-20,000dalton, preferably in the range of 8000-13000 dalton. The base polymerneeds to be semicrystalline in order to have handling integrity. Thehigher is the crystallinity of the polymer, the more plasticizer isneeded to soften the polymer so that the biocompatible, polymericcomposition would have physical properties similar to conventional bonewax.

The Plasticizers

Plasticizers are additives that increase the plasticity or fluidity of amaterial. Suitable plasticizers for the present application include, butare not limited to, polyalkylene glycols (PAG) such as polyethyleneglycol (PEG) and polypropylene glycol (PPG). Suitable molecular weightof PEG for plasticizing the bioabsorbable polymer of the presentapplication (e.g., TPDX polymers) include PEG with a number averagemolecular weight in the range of 1,000-20,000 dalton, preferably in therange of 2,000-15,000 dalton. In one embodiment, the PEG has a numberaverage molecular weight of 15,000 dalton. In other embodiments, the PEGhas a number average molecular weight of 1,000 or 4,600 dalton. In otherembodiments, the PEG has a weight average molecular weight of1,000-4,000 dalton. In some embodiments, the polymer-to-plasticizerweight ratio in the biocompatible, polymeric composition is in the rangeof 1000:1 to 1:1, preferably in the range of 100:1 to 3:1. In someembodiments, biocompatible, polymeric composition formulations withdesired compliant handling characteristics (i.e., feel like a putty) areprepared by combining a purified solid form of the base polymer (e.g.,TPDX) which is usually in powder form following purification, with 1-25%w/w of PEG.

The Therapeutic Agents

The therapeutic agents may include anti-inflammatory agents,anti-adhesion agents, osteogenesis and calcification promoting agents,antibacterial agents and antibiotics, immunosuppressive agents,immunostimulatory agents, anesthetics, cell/tissue growth promotingfactors, anti-scarring agents, anti-neoplastic and anticancer agents.

Examples of anti-inflammatory agents include, but are not limited to,non-steroidal anti-inflammatory drugs such as ketorolac, naproxen,diclofenac sodium and flurbiprofen.

Examples of anti-adhesion agents include, but are not limited to talcumpowder, metallic beryllium and oxides thereof, copper, silk, silica,crystalline silicates, talc, quartz dust, and ethanol.

Examples of osteogenesis or calcification promoting agents include, butare not limited to, bone fillers such as hydroxyapatite, tricalciumphosphate, and calcium sulfate, bone morphogenic proteins (BMPs), suchas BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7.

Examples of antibacterial agents and antibiotics include, but are notlimited to, erythromycin, penicillins, cephalosporins, doxycycline,gentamicin, vancomycin, tobramycin, clindamycin and mitomycin.

Examples of immunosuppressive agents include, but are not limited to,glucocorticoids, alkylating agents, antimetabolites, and drugs acting onimmunophilins such as ciclosporin and tacrolimus.

Examples of immunostimulatory agents include, but are not limited to,interleukins, interferon, cytokines, toll-like receptor (TLR) agonists,cytokine receptor agonist, CD40 agonist, Fc receptor agonist,CpG-containing immunostimulatory nucleic acid, complement receptoragonist, or an adjuvant.

Examples of antiseptics include, but are not limited to, chlorhexidineand tibezonium iodide.

Examples of anesthetic include, but are not limited to, lidocaine,mepivacaine, pyrrocaine, bupivacaine, prilocalne, and etidocaine.

Examples of cell growth promoting factors include, but are not limitedto, epidermal growth factors, human platelet derived TGF-β, endothelialcell growth factors, thymocyte-activating factors, platelet derivedgrowth factors, fibroblast growth factor, fibronectin or laminin.

Examples of antineoplastic/anti-cancer agents include, but are notlimited to, paclitaxel, carboplatin, miconazole, leflunamide, andciprofloxacin.

Examples of anti-scarring agents include, but are not limited tocell-cycle inhibitors such as a taxane, immunomodulatory agents such asserolimus or biolimus (see, e.g., paras. 64 to 363, as well as all of US2005/0149158, which is incorporated by reference in its entirety).

It is recognized that in certain forms of therapy, combinations ofagents/drugs in the same polymeric composition can be useful in order toobtain an optimal effect. Thus, for example, an antibacterial and ananti-inflammatory agent may be combined in a single copolymer to providecombined effectiveness.

Method of Making the Biocompatible Polymeric Composition

The base polymers suitable for the biocompatible polymeric compositionof the present application can be synthesized as described in theExamples of the present application. In some embodiments, thebiocompatible polymeric composition of the present application isproduced by blending one or more bioabsorbable polymers with the properamount of a plasticizer. In other embodiments, the biocompatiblepolymeric composition of the present application is produced by forminga prepolymer by admixing para-dioxanone and trimethylene carbonate andpolymerizing with an initiator; and end-capping the prepolymer with acomposition comprising a polylactone. Biocompatible polymericcompositions containing a therapeutic agent can be prepared by thecold-worked or hot-worked method as described in Example 13 of thepresent application, depending on the heat-resistance of the therapeuticagent. For therapeutic agents that are likely to be inactivated by heat,the cold-worked method is preferred. Briefly, the biocompatiblepolymeric composition is completely melted in the absence of thetherapeutic agent. The melted composition is cooled to room temperatureor below to delay crystallization of the polymer in the composition. Incertain embodiments, the cooling is conducted at a rate of about 10° C.per minute. The therapeutic agent is then added to the meltedcomposition at room temperature or below and mixed thoroughly with thecomposition to create a homogeneous blend.

Methods of Using the Biocompatible Polymeric Composition

Another aspect of the present application relates to a method fortreating bleeding from bone or bony structures. The method comprises thestep of administering to a site of bleeding from bone or bony structuresin a subject an effective amount of the biocompatible, polymericcomposition of the present application.

Another aspect of the present application relates to a method forfilling a void or correct a defect in a bone. The method comprisesadministering to a void or defect in a bone of a subject an effectiveamount of the biocompatible, polymeric composition of the presentapplication, such that the void is filled or the defect is corrected.

Another aspect of the present application relates to a method ofdelivering therapeutic agents using the biocompatible, polymericcomposition of the present application. The method comprises the step ofapplying an effective amount of the biocompatible, polymeric compositioncomprising a base polymer and one or more therapeutic agents at atreatment site. The method can be used to effectively plug bleeding bonystructures and eliciting immediate hemostasis, and for the treatment ofconditions such as sternal wound infection (SWI) and osteomylitis.

Another aspect of the present application relates to a method ofreducing the likelihood of sternal wound infection (SWI). The methodcomprises the step of administering to a sternal wound site an effectiveamount of the biocompatible, polymeric composition comprising a basepolymer and one or more anti-infection agents.

SWI is a common complication following cardiothoracic surgery and posesa high risk of morbidity and mortality. Mediastinitis is reported tooccur in up to 5% of patients following cardiac surgery (Baskett R. J.et al. Ann Thorac Surg, 67, 462 (1999)), and approximately 15% ofpatients are readmitted for a recurrent sternal wound infection (Kaye,A. E. et al. Ann Plast Surg, 64, 658 (2010)). Infections are often theresult of staphylococcal bacteria, and unfortunately, treatment of SWIinvolves an invasive procedure of surgical debridement (Douville, E. C.et al. Ann Thorac Surg, 78, 1659 (2004)). A number of risk factors havebeen identified for SWI (Baskett R. J. et al., supra); however, the onlymodifiable factors include the use of bone wax and the use of bilateralmammary arteries in diabetic patients. The use of bone wax in thoracicsurgery can be employed as an aid in prophylactic treatment in additionto the conventional role of bone wax as a hemostatic agent to plug thebleeding sternum. By incorporating antibiotics such as rifampin, whichhas been shown to improve outcomes against staphylococcal SWI (Khanlari,B. et al. J Antimicrob Chemother, 65, 1799 (2010)), bone wax can beengineered as a prophylactic material for use in cardiothoracic surgery.

The present invention is further illustrated by the following exampleswhich should not be construed as limiting. The contents of allreferences, patents and published patent applications cited throughoutthis application, as well as the Figures and Tables are incorporatedherein by reference.

EXAMPLES Example 1 Composition of TPDX Copolymers

TPDX1: A solid, crystalline polyaxial copolymer comprising a polyaxialprepolymer and semicrystalline end graft. The prepolymer consists ofpolymerized para-dioxanone and trimethylene carbonate and is initiatedwith trimethylolpropane. The end graft consists of polymerized L-lactideand para-dioxanone. The prepolymer constitutes approximately 25% by moleof the polymer, and the end-graft constitutes approximately 75% by mole.The composition of the prepolymer is TMC/PDO (17.1/8.6% by mole), andthe end graft composition is L-lactide/PDO (5.9/68.3% by mole).

TPDX2: A solid, crystalline polyaxial copolymer comprising a polyaxialprepolymer and semicrystalline end graft. The prepolymer consists ofpolymerized para-dioxanone and trimethylene carbonate and is initiatedwith trimethylolpropane. The end graft consists of polymerized glycolideand para-dioxanone. The prepolymer constitutes approximately 25% by moleof the polymer, and the end-graft constitutes approximately 75% by mole.The composition of the prepolymer is TMC/PDO (17.1/8.6% by mole), andthe end graft composition is glycolide/PDO (4.5/69.8% by mole).

TPDX3: A solid, crystalline polyaxial copolymer comprising a polyaxialprepolymer and semicrystalline end graft. The prepolymer consists ofpolymerized para-dioxanone and trimethylene carbonate and is initiatedwith trimethylolpropane. The end graft consists of polymerized glycolideand para-dioxanone. The prepolymer constitutes approximately 25% by moleof the polymer, and the end-graft constitutes approximately 75% by mole.The composition of the prepolymer is TMC/PDO (17.1/8.6% by mole), andthe end graft composition is glycolide/PDO (4.5/69.8% by mole). Themonomer to initiator ratio is increased in TPDX3 to increase itsmolecular weight relative to TPDX1.

TPDX5: A solid, crystalline polyaxial copolymer comprising a polyaxialprepolymer and semicrystalline end graft, and a third outer segmentconsisting of poly(trimethylene carbonate). This composition is preparedby taking purified TPDX3 and reacting with trimethylene carbonate toextend the polymer chains with amorphous segments. This polymer has beenprepared by reacting 60.0 grams of TPDX3 with 20.0 grams of trimethylenecarbonate.

TPDX6: A solid, crystalline polyaxial copolymer comprising a polyaxialprepolymer and semicrystalline end graft. The prepolymer consists ofpolymerized para-dioxanone, glycolide and trimethylene carbonate and isinitiated with trimethylolpropane. The end graft consists of polymerizedglycolide and para-dioxanone. The prepolymer constitutes approximately45% by mole of the polymer, and the end-graft constitutes approximately55% by mole. The composition of the prepolymer is Glycolide/TMC/PDO(14.8/14.5/15.8% by mole), and the end graft composition isglycolide/PDO (8.2/46.8% by mole).

TPDX7: A solid, crystalline polyaxial copolymer comprising a polyaxialprepolymer and semicrystalline end graft. The prepolymer consists ofpolymerized para-dioxanone and trimethylene carbonate and is initiatedwith trimethylolpropane. The end graft consists of polymerized glycolideand para-dioxanone. The prepolymer constitutes approximately 25-26% bymole of the polymer, and the end-graft constitutes approximately 74-75%by mole. The composition of the prepolymer is TMC/PDO (16.7/8.3% bymole), and the end graft composition is glycolide/PDO (11.2/63.8% bymole.).

Example 2 Synthesis of TPDX1

A reaction setup comprising a three-neck round bottom flask, a stainlesssteel stirrer, a Teflon stirring adapter, and two gas inlet adapters wasassembled and tested by reducing the pressure of the assembly with avacuum pump to less than 0.5 mm Hg. When acceptable vacuum was obtained,the assembly was purged with nitrogen gas and trimethylene carbonate(37.0 grams), p-dioxanone (18.5 grams, thawed) and trimethylolpropane(8.1 grams) were added to the reaction assembly through a glass funnel.The reaction materials were then dried at 40° C. and 0.15 mm Hg for onehour. The assembly was purged with nitrogen gas, and the temperature wasraised to 100° C. to melt reaction materials. Stirring was initiatedupon melting to mix the reaction materials, and then Tin (II) Ethylhexanoate (1.05 mL, 0.2M in toluene) was added to the flask. Thetemperature was increased to 140° C. to initiate polymerization. As thereaction proceeded at 140° C., samples were taken for analysis by gelpermeation chromatography (GPC) to determine the extent of conversion.The reaction was stopped after 3.5 hours and cooled to room temperatureovernight. The next day, the temperature was increased from roomtemperature to 100° C., and the second charge consisting of p-dioxanone(147.4 grams) and L-lactide (18.1 grams) was added through a glassfunnel to the reaction flask. The reaction contents were stirred for 45minutes at 100° C. to mix thoroughly, and then the temperature wasincreased to 140° C. in order to initiate the synthesis of the end-graftonto the prepolymer. After 4.5 hours, the temperature was decreased toroom temperature. The final product was collected and analyzed by GPCand differential scanning calorimetry (DSC).

Example 3 Synthesis of TPDX2

A reaction setup comprising a three-neck round bottom flask, a stainlesssteel stirrer, a Teflon stirring adapter, and two gas inlet adapters wasassembled and tested by reducing the pressure of the assembly with avacuum pump to less than 0.5 mm Hg. When acceptable vacuum was obtained,the assembly was purged with nitrogen gas and trimethylene carbonate(34.1 grams), p-dioxanone (17.0 grams, thawed) and trimethylolpropane(7.466 grams) were added to the reaction assembly through a glassfunnel. The reaction materials were then dried at room temperature and0.05 mm Hg for 30 minutes. The assembly was purged with nitrogen gas,and the temperature was raised to 115° C. to melt reaction materials.Stirring was initiated upon melting to mix the reaction materials, andthen Tin (II) Ethyl hexanoate (0.944 mL, 0.2M in toluene) was added tothe flask. The temperature was increased to 140° C. to initiatepolymerization. As the reaction proceeded at 140° C., samples were takenfor analysis by gel permeation chromatography (GPC) to determine theextent of conversion. The reaction was allowed to continue overnight at140° C. The next day, a second charge consisting of p-dioxanone (138.9grams) and glycolide (10.1 grams) was added through a glass funnel tothe reaction flask. The reaction proceeded at 140° C. for 6 hours, andthen the temperature was decreased to 100° C. and held at thattemperature for 17 hours. While still hot, the polymer was poured out ofthe reaction flask into a clean jar. The final product was analyzed byGPC and differential scanning calorimetry (DSC).

Example 4 General Method for Purification of TPDX-Type Copolymers

The unpurified polymer was dissolved in dichloromethane using aconcentration of 0.25 grams polymer per 1 mL of solvent. 100 mL of thissolution was blended with approximately 400 mL of cold isopropyl alcohol(−60° C. to −70° C.), causing polymer to precipitate. The precipitatedpolymer was filtered, and then the polymer was blended again with coldisopropyl alcohol (−60° C. to −70° C.), using approximately 250 mL ofsolvent. The purified polymer was dried in a fume hood for a minimum of12 hours, and then the polymer was transferred to a vacuum oven to dryfurther in order to remove any remaining isopropyl alcohol.

Example 5 General Method for Purification of TPDX-Type Copolymers

The unpurified polymer was dissolved in acetone using a concentration of0.25 grams polymer per 1 mL of solvent. 100 mL of this solution wasblended with approximately 400 mL of cold isopropyl alcohol (−60° C. to−70° C.), causing polymer to precipitate. The precipitated polymer wasfiltered, and then the polymer was blended again with cold isopropylalcohol (−60° C. to −70° C.), using approximately 250 mL of solvent. Thepurified polymer was dried in a fume hood for a minimum of 12 hours, andthen the polymer was transferred to a vacuum oven to dry further inorder to remove any remaining isopropyl alcohol.

Example 6 Alternate General Method for Purification of TPDX-TypeCopolymers

The unpurified polymer was dissolved in dichloromethane using aconcentration of 0.25 grams polymer per 1.0 mL of solvent. 100 mL ofthis solution was blended with approximately 400 mL of cold isopropylalcohol (−60° C. to −70° C.), causing polymer to precipitate. Theprecipitated polymer was filtered and added to a beaker containingapproximately 200 mL of room temperature isopropyl alcohol. The mixturewas stirred for approximately 60 seconds using a spatula, during whichtime the polymer changed from a hard solid to a semi-liquid material atthe higher temperature. The isopropyl alcohol was subsequently decantedfrom the beaker, and the semi-liquid polymer was transferred to a sheetof foil to dry in a fume hood for a minimum of 12 hours. The purifiedpolymer was transferred to a vacuum oven to dry further in order toremove any remaining isopropyl alcohol.

Example 7 General Method for Preparing Blend of Polymer and TherapeuticAgent(s)

Approximately 10.0 grams of polymer was heated in a clean glass jarabove the melting point for at least 5 minutes until the polymer wascompletely molten. The jar was then moved to a freezer (−15° C.) inorder to facilitate the rapid cooling of the polymer from elevatedtemperatures. Upon successful cooling of the polymer, the therapeuticagent(s) were added to the jar containing cold polymer and mixedthoroughly to disperse the therapeutic agent(s) throughout the polymericmatrix. The new blend was then transferred to a vacuum oven for shortterm storage.

Example 8 Another General Method for Preparing Blend of Polymer andTherapeutic Agent(s)

Approximately 10.0 grams of polymer was heated in a clean glass jarabove the melting point for at least 5 minutes until the polymer wascompletely molten. The jar was then submerged in cold bath containingice water in order to facilitate the cooling of the polymer fromelevated temperatures. Upon successful cooling of the polymer, thetherapeutic agent(s) were added to the cold polymer and mixed thoroughlyto disperse the therapeutic agent(s) throughout the polymeric matrix.The new blend was then transferred to a vacuum oven for short termstorage. (Therapeutic agents may include anti-inflammatory agents,anesthetic agents, cell growth promoting agents, antimicrobial agents(such as doxycycline, gentamicin, vancomycin, tobramycin, clindamycin,and mitomycin), antiviral agents and antineoplastic agents.)

Example 9 Method for Preparing Blend of TPDX1 with Polyethylene Glycol(AvgM_(n)=4,600)

Approximately 9.0 grams of TPDX1 was added to a clean glass jar andheated at 130° C. for 30 minutes in order to fully melt the polymersample. Approximately 1.0 grams of Polyethylene glycol (averageM_(n)=4,600) was added to the molten TPDX1 while hot and mixedthoroughly with a spatula for approximately 60 seconds. The jar wassealed with a lid, and then the blend was allowed to cool slowly to roomtemperature for 24 hours as it hardened.

Example 10 Method for Preparing Blend of TPDX1 with TPDX7

Approximately 5.0 grams of TPDX1 and 5.0 grams of TPDX7 were added to aclean glass jar and heated at 130° C. for 30 minutes in order to fullymelt both polymers. While hot, the polymers were mixed thoroughly with aspatula for approximately 60 seconds. The jar was sealed with a lid, andthen the blend was allowed to cool slowly to room temperature for 24hours as it hardened.

Example 11 Synthesis of TPDX7: A Polyaxial, Semicrystalline, DiblockCopolymer Composed of Para-dioxanone, Trimethylene Carbonate, andGlycolide

A reaction setup comprising a three-neck round bottom flask, a stainlesssteel stirrer, a Teflon stirring adapter, and two gas inlet adapters wasassembled and tested by reducing the pressure of the assembly with avacuum pump to less than 0.5 mm Hg. When acceptable vacuum was obtained,the assembly was purged with nitrogen gas and trimethylene carbonate(32.8 grams), p-dioxanone (16.4 grams, thawed) and trimethylolpropane(7.393 grams) were added to the reaction assembly through a glassfunnel. The reaction materials were then dried at room temperature and0.05 mm Hg for 30 minutes. The assembly was purged with nitrogen gas,and the temperature was raised to 100° C. to melt the reactionmaterials. Stirring was initiated upon melting to mix the reactionmaterials, and then Tin (II) Ethyl hexanoate (1.0 mL, 0.2M in toluene)was added to the flask. The temperature was increased to 160° C. toinitiate polymerization. As the reaction proceeded at 160° C., sampleswere taken for analysis by gel permeation chromatography (GPC) todetermine the extent of conversion. The reaction temperature wasdecreased to 140° C. and was allowed to continue overnight. The nextday, a second charge consisting of p-dioxanone (125.6 grams) andglycolide (25.2 grams) was added through a glass funnel to the reactionflask. The reaction proceeded at 140° C. for 8 hours, and then thetemperature was decreased to 120° C. and held at that temperature for 48hours. While still hot, the polymer was poured out of the reaction flaskinto a clean jar. The final product was analyzed by GPC and differentialscanning calorimetry (DSC).

Example 12 DSC Analysis, GPC Analysis and Streak Test of TPDX1 and TPDX2

Purified TPDX1 and TPDX2 polymers were analyzed by differential scanningcalorimetry (DSC) and gel permeation chromatography (GPC) analysis.Functional streak tests were performed on all polymers in order toqualitatively compare novel compositions to commercial ETHICON® bonewax. Streak tests were performed by kneading polymer by hand for 5minutes to increase temperature, then spreading a streak of polymeracross a clean glass surface. The spreadability of each polymer wasassessed visually.

As shown in Table 1, TPDX1 melts at 70° C. with a heat of fusion equalto 53 J/g, and TPDX2 melts at 60° C. with a heat of fusion of 44 J/g.GPC analysis indicates that of the two polymers, TPDX2 had a lowerpolydispersity (see Table 2). Streak tests that were performed with bothpolymer prototypes demonstrate that TPDX1 performs more comparably tocommercial bone wax. TPDX1 made a relatively clean, smooth streak acrossthe glass plate, whereas TPDX2 produced uneven streak marks (see FIG.1).

TABLE 1 Thermal data analysis of bone wax polymers. Bone Wax FormulationTm (° C.) ΔH (J/g) Ethicon ® Bone Wax 54, 60 142 TPDX1 70 53 TPDX2 60 44

TABLE 2 GPC results for bone wax formulations. Composition Mn Mw PDITPDX1 4,900 9,000 1.8 TPDX2 5,500 7,100 1.3

Example 13 Localized Delivery of Therapeutic Agents with Synthetic BoneWax

Formulation Preparation. Bone wax formulations were prepared bycold-worked and hot-worked methods. Cold-worked (CW) formulations wereprepared by adding 1.0 gram of polymer to a glass vial that was sealedand heated at 100° C. for 30 minutes to completely melt the sample. Hotvials were quench-cooled to delay crystallization of the polymer. Vialswere equilibrated at room temperature for 30 minutes, then 50 mg of testdrug 1 and 50 mg of test drug 2 were added to each vial and mixedthoroughly to create a homogeneous blend. Hot-worked (HW) formulationswere prepared by weighing polymer and drug and adding to the same vialat room temperature. Vials were heated at 100° C. for 30 minutes, thenremoved and mixed to create homogeneous formulations. Upon mixing, allpolymer-drug formulations were stored immediately in a room temperaturevacuum oven (vacuum >28 in. H20) for at least 24 hours.

HPLC Analysis. Test drug 1 and drug 2 were extracted from bone waxformulations using acetonitrile and analyzed by HPLC to determine drugstability. A standard solution of drug 1 and drug 2 was analyzed by HPLCand used to create a photodiode array (PDA) spectra match library. Drugstability was determined by comparison of drug 1 and drug 2 PDA spectrafrom the match library to the PDA spectra at appropriate retention timesfrom exploratory extract samples. When analyzing PDA results, a matchangle value below the match threshold value indicated that theexploratory PDA was statistically analogous to the match library PDA forthe particular drug in question, resulting in positive molecularidentification.

The results of HPLC PDA analysis are summarized in Tables 3 and 4.According to HPLC PDA analysis, extracts from cold-worked formulationscontained stable drug 1 and drug 2 at T=0 and T=7 days, whereas extractsfrom hot-worked formulations at T=0 contained stable drug 2 and degradeddrug 1. Of the two methods investigated for the preparation of bonewax-drug formulations, only cold-working resulted in a completely stablebone wax-drug formulation over 7 days. This novel material shows greatpromise, not only as a bioresorbable substitute for commerciallyavailable bone wax, but also as a vehicle to release prophylactic agentsfor the prevention of SWI.

TABLE 3 PDA results from HPLC analysis of drug 1 control sample and drug1 extracts from hot-worked (HW) and cold-worked (CW) samples. RetentionMatch Match Sample Time (min) Angle Threshold Drug 1 Control 15.2800.095 1.206 Drug 1, HW, T = 0 15.201 7.175 1.202 Drug 1, CW, T = 715.306 0.154 1.201

TABLE 4 PDA results from HPLC analysis of drug 2 control sample and drug2 extracts from hot-worked (HW) and cold-worked (CW) samples RetentionMatch Match Sample Time (min) Angle Threshold drug 2 Control 6.856 0.0271.138 HW, T = 0 6.790 0.295 1.206 CW, T = 7 6.855 0.201 1.136

The above description is for the purpose of teaching the person ofordinary skill in the art how to practice the present invention, and itis not intended to detail all those obvious modifications and variationsof it which will become apparent to the skilled worker upon reading thedescription. It is intended, however, that all such obviousmodifications and variations be included within the scope of the presentinvention, which is defined by the following claims. The claims areintended to cover the components and steps in any sequence which iseffective to meet the objectives there intended, unless the contextspecifically indicates the contrary.

What is claimed is:
 1. A biocompatible, surgical bone wax composition,comprising: a base polymer comprising: (i) a prepolymer comprisingpara-dioxanone (PDO) and trimethylene carbonate (TMC) and atrimethylolpropane initiator, comprising 10-40% by mole of the surgicalbonewax composition; and (ii) an end-graft polymer comprising apolylactone comprising 60-90% by mole of the surgical bone waxcomposition, wherein said polyactone comprises a copolymer of (1)para-dioxanone repeat units, and (2) repeat units of at least one othercyclic monomer.
 2. The composition according to claim 1, wherein saidend-graft polymer further comprises para-dioxanone.
 3. The compositionaccording to claim 1, wherein said at least one other cyclic monomer isselected from the group consisting of L-lactide, D-lactide, D,L-lactide,glycolide, caprolactone and trimethylene carbonate.
 4. The compositionaccording to claim 1, further comprising a plasticizer that reducescrystallinity of the base polymer.
 5. The composition according to claim4, wherein said plasticizer is a polyalkylene glycol.
 6. The compositionaccording to claim 5, wherein said polyalkylene glycol is polyethyleneglycol.
 7. The composition according to claim 6, wherein the numberaverage molecular weight of said polyethylene glycol is between about1,000 and 20,000 dalton.
 8. The composition according to claim 4,wherein said plasticizer is combined with said base polymer at a weightratio from about 1:1000 to about 1:1.
 9. The composition according toclaim 1, wherein the number average molecular weight of said compositionis between about 3,000 to 10,000 dalton, and the weight averagemolecular weight of said compositions is between about 5,000 and 20,000dalton.
 10. The composition according to claim 9, wherein the numberaverage molecular weight of said composition is between about 4,000 and7,000, and the weight average molecular weight of said composition isbetween about 8,000 and 13,000.
 11. The composition according to claim1, further comprising a therapeutic agent.
 12. The composition accordingto claim 11, wherein said therapeutic agent is selected from the groupconsisting of anti-inflammatory agents, anti-adhesion agents,osteogenesis and calcification promoting agents, antibacterial agentsand antibiotics, immunosuppressive agents, immunostimulatory agents,anesthetics, cell/tissue growth promoting factors, anti-scarring agents,anti-neoplastic and anticancer agents.
 13. The composition according toclaim 12, wherein said therapeutic agent is an antibiotics selected fromthe group consisting of erythromycin, penicillins, cephalosporins,doxycycline, gentamicin, vancomycin, tobramycin, clindamycin andmitomycin.
 14. The composition according to claim 12, wherein saidtherapeutic agent is a osteogenesis and calcification promoting agentselected from the group consisting of hydroxyapatite and collagen.
 15. Amethod for treating bleeding from bone or bony structures, comprising:administering to a site of bleeding from bone or bony structures in asubject an effective amount of the composition according to claim
 1. 16.The method according to claim 15, wherein said bleeding is due toseparation or cracking of the sternum.
 17. A method for filling a voidor defect in a bone, comprising administering to a void or defect in abone of a subject an effective amount of the composition according toclaim 1, such that said void or defect is filled.